We propose to isolate and identify novel AMPA receptor blocking conopeptides from marine cone snail venom for chronic pain intervention. Conopeptides are bioactive peptides from marine cone snail venom, and AMPA (a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors are non-NMDA glutamate type receptors, which mediate fast signal transmission in nociceptive pathways. AMPA receptor blocking conopeptides will be isolated from the venom and sequenced for their amino acid composition. AMPA receptor blocking drugs for the treatment of chronic pain exist, but are limited in use by a high incidence of unwanted side effects, and lack of specificity for only the AMPA type glutamate receptor. AMPA receptor involvement in chronic pain transmission occurs in the dorsal root ganglia, dorsal horn and spinal cord. Novel conopeptides that are selective for blocking AMPA receptors will provide analgesia in the treatment of chronic pain. In Phase I we will: 1) establish biologically active AMPA receptor blocking venom fractions, 2) purify identified venom fractions and sequence the individual peptides that block AMPA receptors, 3) determine the specific AMPA receptor subunits acted on by the AMPA blocking peptides. In Phase II we will determine the analgesic activity of AMPA receptor blocking conopeptides in vivo rodent models of chronic pain. PROPOSED COMMERCIAL APPLICATION: The treatment and management of chronic pain afflicts approximately 34 million Americans resulting in costs of $40 billion annually. The incidence of chronic pain is predicted to increase due to a rise in the aging population. In many instances chronic pain is not well managed through current therapies, especially due to the addictive nature of narcotics used to treat chronic pain. Therefore, an increasing demand for non-opioid analgesics could be met by effective conopeptide analgesics in this market.